Fibroblast growth factor receptors in cancer: genetic alterations,diagnostics, therapeutic targets and mechanisms of resistance

Fibroblast growth factor receptors (FGFRs) are aberrantly activated through single-nucleotide variants, gene fusions and copy number amplifications in 5–10% of all human cancers, although this frequency increases to 10–30% in urothelial carcinoma and intrahepatic cholangiocarcinoma. We begin this review by highlighting the diversity of FGFR genomic alterations identified in human cancers and the current challenges associated with the development of clinical-grade molecular diagnostic tests to accurately detect these alterations in the tissue and blood of patients. The past decade has seen significant advancements in the development of FGFR-targeted therapies, which include selective, non-selective and covalent small-molecule inhibitors, as well as monoclonal antibodies against the receptors. We describe the expanding landscape of anti-FGFR therapies that are being assessed in early phase and randomised controlled clinical trials, such as erdafitinib and pemigatinib, which are approved by the Food and Drug Administration for the treatment of FGFR3-mutated urothelial carcinoma and FGFR2-fusion cholangiocarcinoma, respectively. However, despite initial sensitivity to FGFR inhibition, acquired drug resistance leading to cancer progression develops in most patients. This phenomenon underscores the need to clearly delineate tumour-intrinsic and tumour-extrinsic mechanisms of resistance to facilitate the development of second-generation FGFR inhibitors and novel treatment strategies beyond progression on targeted therapy.Subject terms: Cancer, Cancer     

Patient navigation across the cancer care continuum: An overview of systematic reviews and emerging literature

Patient navigation is a strategy for overcoming barriers to reduce disparities and to improve access and outcomes. The aim of this umbrella review was to identify, critically appraise, synthesize, and present the best available evidence to inform policy and planning regarding patient navigation across the cancer continuum. Systematic reviews examining navigation in cancer care were identified in the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, Cumulative Index of Nursing and Allied Health (CINAHL), Epistemonikos, and Prospective Register of Systematic Reviews (PROSPERO) databases and in the gray literature from January 1, 2012, to April 19, 2022. Data were screened, extracted, and appraised independently by two authors. The JBI Critical Appraisal Checklist for Systematic Review and Research Syntheses was used for quality appraisal. Emerging literature up to May 25, 2022, was also explored to capture primary research published beyond the coverage of included systematic reviews. Of the 2062 unique records identified, 61 systematic reviews were included. Fifty-four reviews were quantitative or mixed-methods reviews, reporting on the effectiveness of cancer patient navigation, including 12 reviews reporting costs or cost-effectiveness outcomes. Seven qualitative reviews explored navigation needs, barriers, and experiences. In addition, 53 primary studies published since 2021 were included. Patient navigation is effective in improving participation in cancer screening and reducing the time from screening to diagnosis and from diagnosis to treatment initiation. Emerging evidence suggests that patient navigation improves quality of life and patient satisfaction with care in the survivorship phase and reduces hospital readmission in the active treatment and survivorship care phases. Palliative care data were extremely limited. Economic evaluations from the United States suggest the potential cost-effectiveness of navigation in screening programs.     

Replicative senescence of human dermal fibroblasts affects structural and functional aspects of the Golgi apparatus

It is well recognized that the world population is ageing rapidly. Therefore, it is important to understand ageing processes at the cellular and molecular levels to predict the onset of age‐related diseases and prevent them. Recent research has focused on the identification of ageing biomarkers, including those associated with the properties of the Golgi apparatus. In this context, Golgi‐mediated glycosylation of proteins has been well characterized. Additionally, other studies show that the secretion of many compounds, including pro‐inflammatory cytokines and extracellular matrix–degrading enzymes, is modified during ageing, resulting in physical and functional skin degradation. Since the Golgi apparatus is a central organelle of the secretory pathway, we investigated its structural organization in senescent primary human dermal fibroblasts using confocal and electron microscopy. In addition, we monitored the expression of Golgi‐related genes in the same cells. Our data showed a marked alteration in the Golgi morphology during replicative senescence. In contrast to its small and compact structure in non‐senescent cells, the Golgi apparatus exhibited a large and expanded morphology in senescent fibroblasts. Our data also demonstrated that the expression of many genes related to Golgi structural integrity and function was significantly modified in senescent cells, suggesting a relationship between Golgi apparatus function and ageing.     

Lipoprotein Lipase Overexpression in Skeletal Muscle Attenuates Weight Regain by Potentiating Energy Expenditure

Moderate weight loss improves numerous risk factors for cardiometabolic disease; however, long-term weight loss maintenance (WLM) is often thwarted by metabolic adaptations that suppress energy expenditure and facilitate weight regain. Skeletal muscle has a prominent role in energy homeostasis; therefore, we investigated the effect of WLM and weight regain on skeletal muscle in rodents. In skeletal muscle of obesity-prone rats, WLM reduced fat oxidative capacity and downregulated genes involved in fat metabolism. Interestingly, even after weight was regained, genes involved in fat metabolism were also reduced. We then subjected mice with skeletal muscle lipoprotein lipase overexpression (mCK-hLPL), which augments fat metabolism, to WLM and weight regain and found that mCK-hLPL attenuates weight regain by potentiating energy expenditure. Irrespective of genotype, weight regain suppressed dietary fat oxidation and downregulated genes involved in fat metabolism in skeletal muscle. However, mCK-hLPL mice oxidized more fat throughout weight regain and had greater expression of genes involved in fat metabolism and lower expression of genes involved in carbohydrate metabolism during WLM and regain. In summary, these results suggest that skeletal muscle fat oxidation is reduced during WLM and regain, and therapies that improve skeletal muscle fat metabolism may attenuate rapid weight regain.     

A Perioperative Care Display for Understanding High Acuity Patients

Background  The data visualization literature asserts that the details of the optimal data display must be tailored to the specific task, the background of the user, and the characteristics of the data. The general organizing principle of a concept-oriented display is known to be useful for many tasks and data types. Objectives  In this project, we used general principles of data visualization and a co-design process to produce a clinical display tailored to a specific cognitive task, chosen from the anesthesia domain, but with clear generalizability to other clinical tasks. To support the work of the anesthesia-in-charge (AIC) our task was, for a given day, to depict the acuity level and complexity of each patient in the collection of those that will be operated on the following day. The AIC uses this information to optimally allocate anesthesia staff and providers across operating rooms. Methods  We used a co-design process to collaborate with participants who work in the AIC role. We conducted two in-depth interviews with AICs and engaged them in subsequent input on iterative design solutions. Results  Through a co-design process, we found (1) the need to carefully match the level of detail in the display to the level required by the clinical task, (2) the impedance caused by irrelevant information on the screen such as icons relevant only to other tasks, and (3) the desire for a specific but optional trajectory of increasingly detailed textual summaries. Conclusion  This study reports a real-world clinical informatics development project that engaged users as co-designers. Our process led to the user-preferred design of a single binary flag to identify the subset of patients needing further investigation, and then a trajectory of increasingly detailed, text-based abstractions for each patient that can be displayed when more information is needed.     

The Moral Status of Human‐Animal Chimeras with Human Brain Cells

While there is not unanimity (across time or cultures), almost all who read this commentary will think that both they and a toddler have a moral status higher than that of a rat. For instance, they will think that a third party who has to choose whom to save from death should choose them over the rat, and the toddler over the rat. But what is it about humans that gives us this greater moral status? This question is particularly pressing when considering that scientists have begun creating human‐animal chimeras with brains composed partly or wholly of human cells. In “Human‐Animal Chimeras: The Moral Insignificance of Uniquely Human Capacities,” Julian Koplin focuses on the moral implications of such experiments and those that use (or plan to use) these chimeras to study diseases and treatments. How should we understand the concerns about moral status that have been raised about such chimeras? In this commentary, I interpret these concerns differently from Koplin and respond to his suggestion that the greater one's ability to draw value from certain kinds of conscious experiences, the greater one's moral status.